Light adaptation is the ability of a photoreceptor to make biochemical adjustments that enable it to detect changes in illumination even in the presence of what would otherwise be a saturating stimulus. A cyclic GMP-mediated enzymatic pathway is used to detect light in rod and cone photoreceptors. One of the biochemical reactions that initiates light adaptation is a Ca2+-mediated feedback pathway that regulates synthesis of cyclic GMP by guanylyl cyclase. The aims of this application are to: (i) understand at a structural level how photoreceptor membrane guanylyl cyclases are regulated by Ca2+ and Ca2+-binding proteins; (ii) understand at the molecular level how mutations in a photoreceptor guanylyl cyclase cause a dominant degenerative disease of the retina, Autosomal Dominant Cone-Rod Dystrophy; and (iii) understand at the physiological level how regulation of cyclic GMP synthesis determines how a photoreceptor adapts to light and how well it returns to the dark state following illumination. These studies will provide fundamental information about how photoreceptors detect light and they will provide insights into the molecular basis of inherited diseases of the retina.